This invention relates generally to proliferative diseases such as cancer and, more specifically, to tumor suppressor molecules that can be used to diagnose and treat proliferative diseases.
Cancer is one of the leading causes of death in the United States. Each year, more than half a million Americans die from cancer, and more than one million are newly diagnosed with the disease. Cancerous tumors result when a cell escapes from its normal growth regulatory mechanisms and proliferates in an uncontrolled fashion. Tumor cells can metastasize to secondary sites if treatment of the primary tumor is either not complete or not initiated before substantial progression of the disease. Early diagnosis and effective treatment of tumors is therefore essential for survival.
Cancer involves the clonal replication of populations of cells that have gained competitive advantage over normal cells through the alteration of regulatory genes. Regulatory genes can be broadly classified into xe2x80x9concogenesxe2x80x9d which, when activated or overexpressed promote unregulated cell proliferation, and xe2x80x9ctumor suppressor genesxe2x80x9d which, when inactivated or underexpressed fail to prevent abnormal cell proliferation. Loss of function or inactivation of tumor suppressor genes is thought to play a central role in the initiation and progression of a significant number of human cancers.
A number of tumor suppressor genes have been identified that, when inactivated, are involved in the initiation or progression of human cancers. Known tumor suppressor genes include, for example, RB, p53, DCC, APC/MCC, NF1, NF2, WT1, VHL, BRCA1, MST1 and WAF1/CIP1. Approaches for treating cancer by modulating the function of certain of these tumor suppressor genes, either with pharmaceutical compounds or by gene therapy methods, have yielded promising results in animal models and in human clinical trials.
Approaches for diagnosing and prognosing cancer by identifying mutations in known tumor suppressor genes have also been developed. For example, identifying individuals containing germline mutations in known tumor suppressor genes has permitted the identification of individuals at increased risk of developing cancer. Such individuals are then closely monitored or treated prophylactically to improve their chance of survival. Identifying the pattern of alterations of known tumor suppressor genes in biopsy samples is also being used to determine the presence or stage of a tumor. Being able to determine whether a cancer is benign or malignant, at an early or late stage of progression, provides the patient and clinician with a more accurate prognosis and can be used to determine the most effective treatment.
In view of the importance of tumor suppressor molecules in the detection and treatment of cancer, there exists a need to identify additional tumor suppressor nucleic acids and polypeptides. The present invention satisfies this need and provides related advantages as well.
The invention provides substantially pure tumor suppressor nucleic acid molecules. In one embodiment, the invention provides a substantially pure tumor suppressor nucleic acid molecule having at least fifteen contiguous nucleotides of SEQ ID NO:2, or a functional fragment thereof. In another embodiment, the invention provides a substantially pure nucleic acid molecule having substantially the same nucleic acid sequence as SEQ ID NO:5, or a functional fragment thereof. In yet another embodiment, the invention provides a substantially pure tumor suppressor nucleic acid molecule having at least fifteen contiguous nucleotides of SEQ ID NO:4, or a functional fragment thereof.
The invention also provides substantially pure hairpin ribozyme nucleic acid molecules, containing a sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3.
The invention further provides a substantially pure tumor suppressor polypeptide having substantially the same amino acid sequence as SEQ ID NO:6, or a functional fragment thereof. A substantially pure antibody or antigen binding fragment reactive with the tumor suppressor polypeptide is also provided.
Also provided are methods of detecting a neoplastic cell in a sample. In one embodiment, the method consists of contacting the sample with a detectable agent specific for a tumor suppressor nucleic acid of the invention and detecting the nucleic acid molecule in the sample, wherein altered expression or structure of the nucleic acid molecule indicates the presence of a neoplastic cell in said sample. In another embodiment, the method consists of contacting the sample with a detectable agent specific for a tumor suppressor polypeptide of the invention and detecting the polypeptide in the sample, wherein altered expression or structure of the polypeptide indicates the presence of a neoplastic cell in the sample.